Devices and methods for treating maxillary sinus disease

ABSTRACT

Devices and methods are described for improving drainage and/or aeration of maxillary sinuses and for treating maxillary sinus disease. Spacer devices are implanted through natural or man-made openings in the maxillary sinus. In some embodiments, the spacer device is loaded with a therapeutic substance which then exits the device over a desired time period to treat maxillary sinus disease.

RELATED APPLICATIONS

This is a continuation in part of copending U.S. patent application Ser.No. 12/100,361 filed Apr. 9, 2008, (issued as U.S. Pat. No. 8,864,787 onOct. 21, 2014), which claims priority to U.S. Provisional PatentApplication Ser. No. 60/922,730 Apr. 9, 2007 and is acontinuation-in-part of U.S. patent application Ser. No. 11/544,009,filed Oct. 4, 2006, (issued as U.S. Pat. No. 7,419,497 on Sep. 2, 2008),which is a continuation in part of U.S. patent application Ser. No.11/234,395, filed Sep. 23, 2005, (issued as U.S. Pat. No. 7,410,480 onAug. 12, 2008), which is a continuation in part of U.S. patentapplication Ser. No. 10/829,917, filed Apr. 21, 2004 (issued as U.S.Pat. No. 7,654,997 on Feb. 2, 2010), and Ser. No. 10/912,578 filed Aug.4, 2004, (issued as U.S. Pat. No. 7,361,168 on Apr. 22, 2008). The fulldisclosure of each patent and patent application listed above is herebyexpressly incorporated herein by reference.

TECHNICAL FIELD

The present application relates generally to medical devices and methodsand more particularly to implantable devices for maintaining patency ofmaxillary sinus openings and/or delivering substances to treat maxillarysinus conditions.

BACKGROUND

In humans, the paranasal sinuses include several pairs of right and leftsinus cavities, primarily the frontal, ethmoid, sphenoid and maxillarysinus cavities. Of these, the maxillary sinuses are the largest and themost common site for sinus infections.

The maxillary sinuses are located on either side of the nasal canal,below the eye socket and behind the cheekbone. Normally, each maxillarysinus has a natural ostium, which is an opening through which mucusdrains from the sinus cavity into the nasal canal and through which airenters the sinus cavity. If the natural ostium of a maxillary sinusbecomes obstructed due to microbial infection, chronic allergicinflammation or anatomical deformity (e.g., a deviated septum), theoutflow of mucus and inflow of air may be impaired, thereby giving riseto a condition known as maxillary sinusitis. Less frequently, dentaldisease affecting the upper molar or bicuspid teeth, which are locatedjust inferior to each maxillary sinus, may cause maxillary sinusitis.

In cases where maxillary sinusitis cannot be successfully treated withmedical therapy (e.g., antibiotics, decongestants and steroid nasalsprays), surgery or catheter-based interventions are sometimesperformed. The surgical approaches to treatment of maxillary sinusitishave included functional edoscopic sinus surgery (FESS), wherein anendoscope and various surgical instruments are inserted through thenostril and used to cut and/or remove bone and soft tissue in an effortto improve drainage and aeration of the maxillary sinus. In recentyears, catheter-based approaches have been developed as alternatives tothe cutting and removal of bone and soft tissue in the typical FESSprocedure. In these catheter-based approaches, a dilator such as theballoon of a balloon catheter is maneuvered into the natural ostium ofthe maxillary sinus and used to dilate the natural ostium. Examples ofsuch catheter-based procedures and related devices useable for treatmentof maxillary sinusitis are described in U.S. Pat. Nos. 7,316,168;7,500,971; 7,419,497; 7,462,175; and 7,410,480; and U.S. PatentApplication Publication Nos. 2006/0004286, now U.S. Pat. No. 7,720,521;2006/0063973; 2006/0210605, now U.S. Pat. No. 7,803,150; 2007/0129751,now U.S. Pat. 8,894,614; 2007/0135789, now U.S. Pat. No. 8,858,586;2007/0167682; 2007/0208252; 2007/0208301, now U.S. Pat. No. 8,951,225;2007/0293727, now U.S. Pat. No. 9,265,407; 2008/0097154, now U.S. Pat.No. 8,080,000; 2008/0097239, now U.S. Pat. No. 7,641,644; 2008/0097295,now U.S. Pat. No. 7,727,186; 2008/0097514, now U.S. Pat. No. 8,088,101;2008/0097515, now U.S. Pat. No. 7,645,272; 2008/0097516, now U.S. Pat.No. 7,727,226; 2008/0103361, now U.S. Pat. No. 8,090,433; 2008/0103521;2008/0119693, now U.S. Pat. No. 8,961,398; 2008/0125626, now U.S. Pat.No. 8,715,169; 2008/0154250, now U.S. Pat. No. 8,142,422; 2008/0195041,now U.S. Pat. No. 8,747,389; 2008/0228085; 2008/0234720, now U.S. Pat.No. 8,123,722; 2009/0187098, now U.S. Pat. No. 9,101,384; 2008/0275483;2008/0281156, now U.S. Pat. No. 9,167,961; 2009/0030274; 2009/0093823,now U.S. Pat. No. 7,771,409 and 2009/0187089, the entire disclosures ofwhich are expressly incorporated herein by reference.

As an alternative to, or in conjunction with, surgery or acatheter-based intervention of the type described above, various devicesand methods have been proposed for delivering drugs or therapeuticagents into certain paranasal sinuses. For example, United States PatentApplication Publication 2004/0116958A1 (Gopferich et al.), now U.S. Pat.No. 8,740,929, issued Jun. 3, 2014 describes tubular spacers formed ofbiodegradable or non-biodegradable polymers and loaded with an activesubstance, such as a corticosteroid or anti-proliferative agent. Aftersurgery has been performed to create a fenestration in a frontal sinus,the space is placed in such fenestration, and the active substance thenpasses out of the spacer. Also, Tarasov D I, et al., “Application ofDrugs Based on Polymers in the Treatment of Acute and Chronic MaxillarySinusitis,” Vestn Otorinolaringol. 1978; 6:45-47 has reported thedelivery of drugs directly into a maxillary sinus cavity for treatmentof sinusitis. Additionally, Deutschmann R, et al., “A Contribution tothe Topical Treatment of [Maxillary] Sinusitis PreliminaryCommunication,” Stomat. 1976; DDR26:585-92 describes the instillation ofa water soluble gelatin mixed with the drug (i.e., Chloramphenicol) intothe maxillary sinus cavity for treatment of maxillary sinusitis. Sincethis gelatin/drug preparation was relatively short acting, the authorsreported that in order to achieve a therapeutic effect it should beinstilled every 2 to 3 days. Devices and methods for sustained deliveryof drugs into paranasal sinus cavities are also described in U.S. Pat.No. 3,948,254 (Zafferoni); U.S. Pat. No. 5,512,055 (Domb, et al.); U.S.Pat. No. 7,361,168 (Makower, et al.); U.S. Pat. No. 7,410,480 (Muni etal.); and U.S. Pat. No. 7,419,497 (Muni, et al.); and United StatesPatent Application Publication Nos.: 2003/0185872A2 (Kochinke), now U.S.Pat. No. 7,074,426; 2005/0245906A1 (Makower, et al.), now U.S. Pat. No.7,361,168; 2005/0043706 (Eaton, et al.), now U.S. Pat. No. 7,544,192;U.S. 2006/0106361A1 (Muni, et al.), now U.S. Pat. No. 7,410,480;2007/0005094 (Eaton, et al.), now U.S. Pat. No. 8,025,635; 2008/0015540(Muni et al.), now U.S. Pat. No. 7,419,497; 2008/0287908 (Muni et al.),now U.S. Pat. No. 8,864,787; 2008/0319424 (Muni et al.); 2009/0028923(Muni, et al.), now U.S. Pat. No. 8,388,642; 2009/0017090 (Arensdorf, etal.), now U.S. Pat. No. 8,535,707; 2009/0047326 (Eaton, et al.), nowU.S. Pat. No. 7,951,132; 2009/0156980 (Eaton, et al.), now U.S. Pat. No.8,858,974 and 2009/0227945 (Eaton, et al.), now U.S. Pat. No. 8,337,454,as well as PCT International Patent Application Publication WO 92/15286(Shikani).

There remains a need for the development of new devices and methodscapable of improving drainage and/or aeration of a maxillary sinusand/or delivering therapeutic substance(s) into a maxillary sinus.

SUMMARY

In one aspect of the present invention, a method for treating a disorderof a maxillary sinus in a human or animal subject may include: formingan opening into a maxillary sinus; advancing a sinus spacer device atleast partway through the opening; deploying at least one retentionmember of the spacer device to retain at least part of the spacer devicewithin the maxillary sinus; introducing a substance into the spacerdevice to expand the device from a collapsed to an expandedconfiguration; and leaving the spacer device in the subject for a periodof between 1 day and 60 days to allow the introduced substance to exitthe spacer device and treat the disorder. In some embodiments of thismethod, the opening into the maxillary sinus may be an opening formedbetween the nasal cavity and a maxillary sinus, through a wall of thesinus. Such opening may be formed by any suitable means, including byinserting a penetrator through an inferior or middle nasal meatus andusing the penetrator to penetrate through an adjacent wall of themaxillary sinus. In other embodiments of this method, the opening into amaxillary sinus may be an opening between the oral cavity and themaxillary sinus (e.g., an opening formed through the buccal or caninefossa). In some embodiments of the method, the opening may be formed ata downward angle to deter gravity-induced slippage of the spacer deviceafter it has been placed through the opening.

In another aspect of the invention, a penetrator that is useable forforming an opening through a wall of a maxillary sinus may include ashaft that has a penetrating distal end and a curve of about 80 degreesto about 110 degrees formed in the shaft. In some embodiments, thepenetrator may be equipped with sensors, reflectors or other apparatusso that it may be used in conjunction with an image guidance system, andthe formation of the opening may be performed as an image guidedprocedure. In some embodiments, the penetrator may have indicator flagon or near the proximal end of the penetrator for indicating thedirection of a curve in the penetrator shaft such that the operator mayuse the flag to determine or confirm the direction of the penetratorcurve while the penetrator is inserted in the subject's body.

In some embodiments, the penetrator may have a lumen. After thepenetrator has been used to penetrate through a wall of the maxillarysinus, a device or substance may be delivered through the penetratorlumen. For example, a guide member (e.g. a guidewire) may be advancedthrough the lumen of the penetrator, through the opening and into themaxillary sinus. Thereafter, the spacer device may be advanced over thatguide member.

In another aspect of the invention, a tubular guide device may be usedto facilitate placement of the spacer within the opening. Such tubularguide device may comprise a tubular shaft having a curve ofapproximately 80 degrees to about 110 degrees, and typicallyapproximately 90 degrees to approximately 100 degrees, formed in adistal portion of the shaft. After the penetrator has been used to formthe opening, the penetrator may be removed, and the tubular guide maythen be advanced to a position where its distal end is within or alignedwith the opening. The spacer device may then be advanced through thetubular guide, and the tubular guide may be removed, leaving the spacerdevice positioned within the opening or maxillary sinus.

In another aspect of the present invention, the spacer device maycomprise an elongate member having a lumen into which a stylet isinserted. A stylet may be inserted into the lumen of the elongate shaftand the spacer, with the stylet positioned therein, may then be advancedthrough the opening. Thereafter, the stylet may be removed. The styletmay comprise an elongate shaft having a proximal end, a distal end and ahub (e.g., a Luer hub) on its proximal end. The shaft of the stylet maybe continually tapered in diameter, or may comprise a series of regionsof progressively smaller diameter, from proximal end to distal end.

In some embodiments, the spacer may comprise an elongate shaft and anexpandable reservoir (e.g., a balloon). The expandable reservoir may beconstructed such that a substance introduced into the reservoir willpass out of (or “exit”) the reservoir while it is implanted within themaxillary sinus. Examples of spacer devices of this type include theRelieva Stratus™ Microflow Spacer, available commercially fromAcclarent, Inc., Menlo Park, Calif., as well as those described in U.S.Pat. Nos. 7,361,168; 7,410,480 and 7,419,497 and U.S. patent applicationSer. Nos. 12/100,361 and 12/341,602, the entire disclosures of which areexpressly incorporated herein by reference.

The reservoir of the spacer device may initially have a relatively smallcross-sectional profile for delivery through the opening formed in themaxillary sinus wall. Thereafter, a fluid (e.g., saline) and/or anactive substance (e.g., drug, biologic, or other therapeutic) may beintroduced into the reservoir causing the reservoir to expand in situ.In at least some embodiments, the reservoir may be constructed so thatit expands to a diameter of from about 3 mm to about 8 mm and a lengthof from about 1 mm to about 100 mm. The permeability of the reservoirmay vary depending on the rate and time over which it is desired for thesubstance to exit the reservoir. For example, in some embodiments, thereservoir may be constructed such that the substance will continue toexit the reservoir for between about 14 days and about 21 days.

The spacer device may additionally comprise at least one positionmaintaining member that abuts, engages or attaches to an adjacentanatomical structure after being deployed to substantially maintain thereservoir in a location within the maxillary sinus. In some embodiments,the position maintaining member(s) may comprise a suture receivingmember (e.g., a loop, slot, bar, etc.) for attaching the device to anadjacent anatomical structure by way of a suture or other connector(e.g., staple, clip, etc.). Additionally or alternatively, the positionmaintaining member(s) may comprise one or more projections (e.g., arms)that protrude from the device such that they will abut or engage (e.g.,frictionally engage or exert pressure upon) an adjacent anatomicalstructure thereby substantially holding the device at the desiredimplantation location. Such projection(s) may be maintained in acollapsed position while at least part of the spacer device is insertedthrough the opening and, thereafter, such projection(s) may be caused totransition to extended position(s) whereby the projection(s) willmechanically contact at least one adjacent anatomical structure. In someembodiments, such projection(s) may comprise first and second laterallyopposed projections (e.g., wire loops or wings) that, when in theirextended positions, span a diameter of about 14 mm to about 20 mm.

In another aspect of the invention, a method for treating a disorder ofa maxillary sinus in a human or animal subject may involve: dilating themaxillary sinus ostium; advancing a sinus spacer device (such as thespacer device summarized above) at least partway through the maxillarysinus ostium; deploying at least one retention member of the spacerdevice to retain at least part of the spacer device within the maxillarysinus; introducing a substance into the spacer device to expand thedevice from a collapsed to an expanded configuration; and leaving thespacer device in the subject for a period of between 1 day and 60 daysto allow the introduced substance to exit the spacer device and treatthe disorder. The dilation of the maxillary sinus ostium, which mayinclude dilation of the ethmoid infundibulum, may be carried out bypositioning an expandable dilator (e.g., a balloon) within the maxillarysinus ostium and, thereafter, expanding the dilator. Specific examplesof dilation devices and methods that may be used for this dilationinclude the Relieva® Sinus Guide Catheters, Relieva® Sinus BalloonCatheters and Relieva Solo Pro™ Sinus Balloon Catheters, availablecommercially from Acclarent, Inc., Menlo Park, Calif. and devicesdescribed in the above-incorporated United States Patents and PatentApplication Publications.

Additional aspects and details of various embodiments are set forthbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a side view of one embodiment of a substance delivery systemcomprising a spacer device in combination with a stylet.

FIG. 1B is a sectional view of the distal end of the spacer device ofFIG. 1A during infusion of a substance into the expandable reservoir ofthe device.

FIG. 1C is a sectional view of the distal end of the spacer device ofFIG. 1A after the expandable reservoir of the device has been filledwith a substance.

FIG. 2 is a side view of the stylet of FIG. 1A.

FIG. 3 is a sectional side view of a guide catheter useable inconjunction with the system of FIG. 1A.

FIG. 4 is a side view of a maxillary insertion probe device useable inperforming methods according to various embodiments.

FIGS. 5A through 5G show steps in one embodiment of a method in which aspacer device is implanted through an opening formed in a wall of amaxillary sinus between the sinus cavity and the nasal cavity.

FIG. 6 is a sectional view of a maxillary sinus ostium showing anotherembodiment of a method in which a spacer device is implanted through theostium of a maxillary sinus.

FIG. 7 is a sectional view of a maxillary sinus ostium showing anotherembodiment of a method in which a spacer device is implanted through anopening formed in a wall of a maxillary sinus between the sinus cavityand the nasal cavity.

DETAILED DESCRIPTION

The following detailed description and the accompanying drawings towhich it refers are intended to describe some, but not necessarily all,examples or embodiments of the invention. The described embodiments areto be considered in all respects only as illustrative and notrestrictive. The contents of this detailed description and theaccompanying drawings do not limit the scope of the invention in anyway.

Spacer/Stylet System:

Referring to FIG. 1A, in one embodiment, embodiment of a system 10 fortreating a maxillary sinus may include an implantable spacer device 11in combination with a stylet 40. (Only the hub 42 of the stylet 40 isvisible in FIG. 1A, but further detail is provided in FIG. 2.) Someembodiments of the system 10 may further include a maxillary insertionguide 50 (FIG. 3) and/or a maxillary insertion probe 60 (FIG. 4).

In one embodiment, the spacer device 11 comprises an elongate flexiblecatheter shaft 12 comprising a proximal shaft portion 12 a and a distalshaft portion 12 b, which may be severed from one another at separationmarker 15 or elsewhere along the shaft 12. The proximal shaft portion 12a and distal shaft portion 12 b may be formed of the same or differentmaterials and may have the same or different dimensions (e.g., diameter,wall thickness, etc.). For example, in some embodiments, the proximalshaft portion 12 a may be made of a suitable biocompatible material suchas polyamide. In some embodiments, the distal shaft portion 12 b may bemade of a more flexible biocompatible material such as nylon. A lumen 13extends continuously through the shaft portions 12 a, 12 b, and a plug23 is mounted in its distal end. The plug 23 may comprise any suitableclosure member, such as a closed end on the tube, an end cap, a masswithin the end of the lumen 13, or any other suitable flow blockingmember. In the particular example shown in the drawings, the plug 23comprises a biocompatible polymeric adhesive disposed within the distalend of lumen 13.

An expandable reservoir 14 is mounted in a collapsed configuration onthe distal shaft portion 12 b near its distal end. Details of thereservoir 14 are seen in FIGS. 1B and 1C. As shown, in this embodiment,the reservoir 14 comprises a balloon that has a cylindrical side wallwherein openings 31 are formed. The reservoir 14 may also be formed ofany suitable biocompatible material and, in some embodiments, maycomprise a balloon formed of non-compliant or semi-compliant materialsuch as Nylon 12. The size of the reservoir 14, the number of reservoirs(such as two or more), and the number and size of the openings 31 mayvary on the basis of the intended implantation location and/or thepotency, viscosity (or particle size) and/or other properties of thesubstance being delivered. For example, in an embodiment of the spacerdevice 11 intended to be passed through an ethmoidotomy channel andpositioned within an ethmoid air cell to treat ethmoid sinusitis, thereservoir 14 may have a length of from about 0.5 cm to about 3.5 cm andtypically approximately 2 cm, and a diameter when fully expanded ofabout 0.1 cm to about 0.5 cm and typically approximately 0.3 cm. Invarious embodiments, the reservoir 14 may include from about 50 to about5000 openings, and each opening may have a diameter from about 5 micronsto about 80 microns. In one embodiment, for example, the reservoir 14includes about 2200 laser cut openings 31 approximately 20 microns indiameter formed in the sidewall of the reservoir 14. The openings 31 canbe staggered one row to the next along the reservoir 14, and there alsocan be openings in the angled or tapered portions of the reservoir 14.

In various embodiments, the reservoir 14 may be used to deliver adesired therapeutic agent or drug at a desired rate over a desired timeperiod. For example, in one embodiment, the reservoir 14 may be used todeliver approximately 0.10 ml of a 40 mg/ml of Triamcinolone Acetonideinjectable suspension, USP (Kenalog®-40, Bristol-Myers Squibb,Somerville, N.J.), Approximately 100 μg of Triamcinolone will exit thisembodiment of the reservoir 14 per day over a period of 14 days.

When used for the treatment of microbial infections, the reservoir 14may be used to deliver a suitable antimicrobial agent (e.g., antibioticor antifungal) alone or in combination with an antiinflammatory, such asa corticosteroid. For example, in patients suffering from maxillarysinusitis of fungal origin, the reservoir 14 may be used to deliver anantifungal agent, such as liposomal or non-liposomal Amphotericin B of0.3 to 1.5 mg/kg, available from Pfizer as Amphocin® anti-fungal.Systemically administered Amphotericin typically has limiteddistribution from the bloodstream across the mucous membranes and viceversa. With this substance delivery spacer device 11, Amphotericin maybe released locally into the mucous membrane where the offending fungalorganisms are present, and therapeutic concentrations of the drug mayremain in the mucus as it is distributed through the sinuses by ciliaryaction. However, substantial amounts of the Amphotericin will not besubstantially absorbed through the sinus mucosa, thereby avoiding thepotential for untoward systemic effects of the Amphotericin such asrenal toxicity. Also, this reservoir 14 may be capable of deliveringsolutions as well as suspensions to the surrounding anatomy. This isespecially useful for delivery of steroids since most steroids areavailable as suspensions.

Also, the reservoir 14 may act as a space occupying device (e.g., astent) after expansion and may itself frictionally engage adjacentanatomical structure(s) to provide a degree of retention at the desiredimplantation location. This aspect of the reservoir 14 may be furtherfacilitated by the provision of surface projections on the reservoir 14.In applications where it is intended only to perform a space occupyingfunction, the reservoir 14 may be loaded with a biologically inert fluid(e.g., saline solution) rather than a solution or suspension thatcontains an active therapeutic agent.

The reservoir 14 also has the advantage of being relatively small indiameter when empty (e.g., collapsed or deflated) and thus can beintroduced or removed easily. In embodiments where the reservoir 14 isformed of non-compliant or semi-compliant material, the reservoir 14will not undergo substantial elastic deformation in the filling processand thus will not exert pressure on its contents in order to expel thedesired substance through openings 31. Rather, the substance in thereservoir 14 will be carried out through the openings 31 by gravity orby being in contact with the mucus that is continually moved along bythe ciliary action in the sinuses. This non-pressurized delivery allowsfor the slow release of the desired substance over several days.

In some other embodiments, the reservoir 14 may be formed of compliantor elastic material with small openings 31 such that the material ofwhich the balloon 14 is formed will contract as substance passes out ofthe openings 31, thereby maintaining pressure within the balloon. In oneembodiment, for example, the reservoir 14 may be 3.0 to 3.5 mm indiameter by 13 mm in length. The reservoir 14 may be made of Nylon 12.In this embodiment, approximately 768 laser cut openings 31 are formedin the side wall of the reservoir 14. The diameter of each laser cutopening 31 is 30 microns. The distal end of shaft 12 is plugged as shownusing Dymax 204CTH adhesive. The distal portion of the shaft 12 is madeof Nylon 12 of an outer diameter of about 0.028 inches and innerdiameter of about 0.020 inches and length of about 17 mm. Elastomericsleeve valve 26 is made of a 3 mm long C-flex medical grade TPE tubing.The tubing may have an inner diameter of about 0.022 inches and wallthickness of about 0.005 inches. Distal radiopaque marker 24 andproximal radiopaque marker 22 are made of a ring of Pt—Ir alloy of outerdiameter about 0.034 inches and inner diameter about 0.030 inches. Theproximal portion of the shaft 12 may be made of polyimide tubing ofouter diameter about 0.0618 inches and inner diameter about 0.052 inchesand length about 20 cm. In one embodiment, a hub 54 (see FIG. 3) is afemale Luer hub made of clear polycarbonate made by Qosina (Edgewood,N.Y.) part number 41519. In one embodiment, each retention wing 18 ismade of a bent loop of Nitinol wire having a diameter of about 0.0086inches The retention wings are oriented at 80° to 90° from thelongitudinal axis of the device. A heat treatment of 520° C. for 20minutes of the nitinol wire loop produces an A_(f) of 20° C. Such adesign of the substance delivery device 11 delivers approximately 100 μgper day of Kenalog®-40 over a period of 14 days.

In one embodiment, the exterior surface of reservoir 14 may be coatedwith a fracturable coating containing one or more therapeutic substancesin a biodegradable matrix. When the reservoir 14 is filled, it expands.This expansion will fracture the fracturable coating such that pieces ofthe coating will enter the surrounding anatomy and will thereafterrelease the therapeutic substance(s) into the anatomy. The fracturablecoating may be made, for example, from gelatin, sodium carboxymethylcellulose or high molecular weight polyethylene glycol (PEG). Such afracturable coating typically dissolves in an aqueous environment.

Referring again to FIGS. 1B and 1C, one embodiment includes an aperture28 in the catheter shaft 12 to facilitate filling the reservoir 14. Avalve 26 allows the substance (or component(s) of the substance) to flowfrom the lumen 13 of the catheter shaft 12 into the reservoir 14 (seeFIG. 1C) but does not allow substantial backflow from the reservoir 14into the lumen 13 (see FIG. 1B). The valve 26 may comprise any suitabletype of one way valve. In the particular embodiment shown, the valve 28comprises an elastomeric sleeve valve made of C-flex® thermoplasticelastomer (Consolidated Polymer Technologies, Inc., Clearwater, Fla.).

In some embodiments, radiopaque markers 22 and 24 are mounted on thedistal catheter shaft portion 12 b to mark the proximal and distal endsof the reservoir 14. The radiopaque markers 22, 24 are preferably formedof material that is clearly more radiopaque than the adjacent materialsand tissues. In this particular non-limiting example the markers 22, 24are formed of Platinum-Iridium alloy.

Referring again to FIG. 1A, the spacer device 11 may incorporateposition maintaining member(s) for holding the device at a desiredlocation within a subject's body. In the non-limiting example shown, theposition maintaining members include a suture loop 20 (e.g., an eyelet)as well as a plurality of projections 18 (e.g., retention wings). Thesuture loop 20 and projections 18 may be formed of supple, flexible,resilient, elastic or superelastic material such as nickel-titaniumalloy (Nitinol) so that they may be collapsed. The projections 18 may bebiased to a deployed (e.g., outwardly protruding) position as seen inFIG. 1A but may sometimes be compressed or bent to a non-deployed (e.g.,collapsed) configuration in which they are substantially parallel andadjacent to the outer surface of the catheter shaft 12. In this manner,as described more fully below, these projections 18 may be constrainedin their non-deployed position during insertion and positioning of thespacer device 11, and thereafter the constraint may be removed (e.g., asthe distal portion of the device emerges out of the distal end of aguide catheter or other tubular delivery guide) allowing theseprojections 18 to spring to or otherwise assume their deployed positionswhere they will abut or engage (e.g., frictionally engage) adjacentanatomical structure(s).

In the particular example shown, the projections 18 are located proximalto reservoir 14 and are in the form of two (2) loops of wire (e.g.,nickel-titanium wire) of 0.0086 inch diameter bent to form diametricallyopposed retention wings. Projections 18 can also be located distal tothe reservoir or both proximal and distal. When the projections 18 arenitinol, cold or warm fluid can be used to transition them to a “softer”state. The length of each projection 18 is determined based on theintended implantation site. For example, in applications where thedevice is inserted through an opening that is less than about 12 mmwide, the projections 18 may be sized such that they span a diameter ofabout 14 mm to about 20 mm when in their deployed positions, thusdeterring slippage of the spacer device 11 out of the opening unless anduntil sufficient extraction force is applied to overcome the bias of theprojections 18. The length and shape of the projections 18 may also bedesigned to cause minimal trauma to the anatomy while ensuring themaximum retention of the spacer device 11 at its intended implantationlocation. In the example shown, the wire loops that form the projections18 and suture loop 20 may be affixed to the outer surface of shaft 12 bywinding the wire around the shaft and securing the wire to the shaftusing a suitable adhesive such as cyanoacrylate, epoxy or UV curableadhesive and/or by mounting a polymeric sleeve or heat shrinkable memberabout the portions of wire that are wound around the shaft 12.

The position maintaining member(s), in one embodiment, comprise smallretention wing(s) made of nitinol wire that spring outward inside of thesinus cavity, but also have a relatively light spring force so that thedevice can be out and removed when desired. Beneficially, the spacerdevice 11 can be removed in a physician's office rather than a surgicalsetting.

Optionally, a flexible distal member 17 (FIG. 1A) may be continuationof, or may extend from, the distal end of the shaft 12 b. This optionaldistal member 17 may have a length of from about 1 cm to about 5 cm andmay facilitate passage of the spacer device 11 through the intendedopening. In embodiments where the distal portion 17 is of sufficientlength, it may become coiled or convoluted within the sinus cavity whenthe spacer device 11 is implanted and, thus, may function as anadditional means for deterring slippage or migration of the spacerdevice 11 while it is implanted.

FIG. 2 shows details of the stylet 40. The stylet 40 comprises anelongate shaft 44 and a hub member 42 on the proximal end of the shaft44. The shaft 44 is sized to be advanced into lumen 13 of the spacerdevice 11 to facilitate insertion of the spacer device 11, as describedmore fully below. The stylet shaft 44 may be formed of any suitablematerial and may be of any suitable construction. In this particularexample, the shaft 44 may be formed of nickel-titanium alloy wire thathas been machined to a series of regions 44 a, 44 b, 44 c, 44 d, 44 ethat are progressively smaller in diameter, thereby giving the distalportion of the shaft 44 greater flexibility than the proximal portion.In the particular example shown, the shaft 44 steps down from a diameterof about 0.033 inch in the proximal shaft region 44 a to a diameter ofabout 0.010 inch at the distal end of the distal shaft region 44 e. Theproximal hub member 42 is configured to abut or seat within he proximalLuer connector 16 of the spacer device 11 when the stylet 40 is fullyinserted into the spacer device 11. The length of the stylet shaft 44may be such that, when the hub 42 is firmly seated within the proximalLuer connector 16 of the spacer device 11, the distal end of the styletshaft 44 will contact or be positioned close to the proximal surface ofplug member 23. In this manner the stylet shaft 44 will occupy all orsubstantially all of the elongate spacer 12 during its insertion.

Maxillary Insertion Guide:

FIG. 3 shows one embodiment of a maxillary insertion guide 50 forfacilitating insertion of the spacer/stylet system 10 through an openingformed in the medial wall of a maxillary sinus. The guide 50 comprisesan elongate shaft 52 having a proximal hub 54 at its proximal end PE, astraight proximal portion PP and a curved distal portion DP. Anysuitable shaft construction may be used. In this particular example, theproximal portion PP of the shaft 52 comprises an outer tube 56, an innertube 58 and an inner liner 59 that lines the inner wall of the innertube 58. The outer tube 56 in this example is formed of stainless steelhypotube having an outer diameter of about 0.134 inch and a length ofabout 85 mm. The inner tube 58 in this example comprises nylon tubinghaving an inner diameter of about 0.087 inch. The liner 59 comprisesthin polytetrofluoroethylene (PTFE) tube. The distal portion DP of theshaft 52 comprises a segment of the inner tube 58 and liner 59 thatprotrudes out of and beyond the distal end of the outer tube 56, asshown. Optionally, the distal-most 3-4 mm of this distal portion DP maybe formed of a material (e.g., an elastomer or hydrogel) that is softerthan the material of the inner tube 58 to deter trauma or abrasion oftissue during insertion of the device. In this non-limiting example, thedistal portion DP of the shaft 52 has a length of about 22 mm, an outerdiameter of about 0.109 inch and an inner diameter of about 0.087 inch.A curve of about 90 degrees to about 100 degrees, with a radius ofcurvature of about 0.3 to about 0.375, is formed in the distal portionDP of the shaft 52.

The inner tube 58 extends through the lumen of the outer tube 56 and adistal portion of the inner liner 59 protrudes out of the distal end ofthe outer tube 56. This distal portion of the inner liner 59 protrudesout of the distal end of the inner tube 58 is bent to form the desiredcurve. In this non-limiting example, the protruding inner liner 59 ofthe inner tube 58 is rigid enough to maintain the desired curved shapebut flexible enough to prevent or reduce unnecessary trauma to theanatomy during use. Also, the inner liner 59 may be rigid enough toenable a user to volitionally displace adjacent paranasal structures asit is being inserted and maneuvered into position.

One or more radiopaque or visual markers may be provided on this guidedevice 50 to facilitate its positioning during use.

Maxillary Insertion Probe:

FIG. 4 shows an example of a maxillary insertion probe 60 that may beused to form an opening through a wall of a maxillary sinus. This probe60 comprises an elongate rigid shaft 62 having a handpiece 64 on itsproximal end and a sharp distal tip 68 at its distal end. A curve 66 ofapproximately 90 degrees to about 110 degrees is formed in the elongateshaft 62 near its distal tip.

Examples of Methods for Treatment of Maxillary Sinusitis Example 1Placement of Spacer Through Antro-Nasal Opening

FIGS. 5A through 5G show one non-limiting example of a method treatingmaxillary sinusitis by forming an opening 70 through a wall W of amaxillary sinus MS and implanting the spacer device 11 such that itsreservoir 14 is within the maxillary sinus MS.

In many subjects, approximately the middle third of the medial wall ofthe maxillary sinus MS also serves as the lateral wall of the inferiormeatus IM. In this example, the maxillary insertion probe 60 is insertedthrough a nostril and is advanced through the inferior meatus IM to aposition where the sharp distal tip 68 of the maxillary insertion probe60 is positioned in contact with the lateral aspect of the inferiormeatus IM forming the maxillary sinus wall W. Optionally, if necessary,the inferior turbinate IT may be medialized. However, in most subjectsthe devices used will be sized to perform this procedure withoutrequiring breaking or medialization of the inferior turbinate IT.

The sharp distal tip 68 of the maxillary insertion probe 60 is thenpushed through the maxillary sinus wall W as shown in FIG. 5A, therebycreating an opening 70 (FIG. 5B) through the wall W. The maxillaryinsertion probe 60 is then removed, as shown in FIG. 5B. Thereafter, asseen in FIG. 5C, the maxillary delivery guide 50 is inserted into theinferior meatus IM and advanced to a position where its distal end DE iswithin or aligned with the opening 70 in the wall W of the maxillarysinus MS. Thereafter, as shown in FIG. 5D, the spacer device 11 with thestylet shaft 44 inserted therein is advanced through the guide 50 suchthat the reservoir 14 and retention members 18 enter the sinus cavity.As the retention members 18 emerge out of the lumen of the guide 60 theywill spring outwardly to their deployed positions. When so deployed, theretention members 18 will span a width that is greater than the diameterof the opening 70, thereby deterring slippage of the spacer device 11out of the maxillary sinus MS. Thereafter, the stylet shaft 44 isretracted and the stylet 40 is removed.

As seen in FIG. 5F, a syringe or other infusion device is then attachedto the Luer connector of the spacer device 11 and is used to infuse adesired substance into the reservoir 14, thereby causing the reservoirto expand. In some cases, a biologically inert fluid (e.g., salinesolution) may be used. In other cases, a fluid containing an activesubstance may be infused so that the active substance will subsequentlypass out of the reservoir 14 into the maxillary sinus MS over a desiredtime period. For example, if used to deliver Triamcinolone AcetonideInjectable Suspension, USP (Kenalog®-40, Bristol-Myers Squibb,Somerville, N.J.), the reservoir 14 may have an overall length of about16 mm and a working length (i.e., the length of the cylindrical sidewall 14 c) of about 13 mm and may be expandable to a fully expandeddiameter of 3.0 to 3.5 mm. Approximately 768 laser cut openings 31 maybe formed in the side wall of the reservoir 14 with the diameter of eachsuch opening 31 being about 40 microns. This particular reservoirdesign, when loaded with 0.31 to 0.35 ml of the 40 mg/ml TriamcinoloneAcetonide injectable suspension, will deliver a dose of approximately100 μg Triamcinolone Acetonide per day for a period of about 28 daysinto the maxillary sinus MS.

As seen in FIG. 5G, after the desired substance has been loaded into thereservoir, the proximal shaft portion 12 a is cut away or otherwisedetached from the distal shaft portion 12 b. Optionally, the remainingdistal shaft portion 12 b may be affixed to an adjacent anatomicalstructure within the nose to further secure the positioning of theimplant. In the non-limiting example shown in FIG. 5G, this isaccomplished by suturing the suture loop 20 to the intranasal septum S.

The implanted portion of the device 12 may remain in place for a desiredtime period and then may be removed. For example, in applications wherethe reservoir 14 is loaded with a steroid and/or antimicrobial agent fortreatment of chronic maxillary sinusitis, it will typically be desirablefor the implanted portion of the device 12 to remain in place with theactive substance(s) exiting the reservoir for approximately 14-28 days.In some subjects, the implanted portion of the device 12 may be allowedto remain in place to perform a spacer function (e.g., maintainingpatency of the opening 70) even after any active substance has passedout of and been depleted from the reservoir 14.

Example 2 Placement of Spacer Through Maxillary Sinus Ostium with orwithout Enlargement of the Ostium

In another embodiment of the present invention, as shown in FIG. 6, thespacer device 11 may be implanted through the maxillary ostium MO of amaxillary sinus MS, with or without dilation or surgical modification ofthe natural ostium MO.

Each maxillary sinus has a natural maxillary sinus ostium MO throughwhich secretions drain from the maxillary sinus cavity into the nose.The natural ostium is formed by an opening in bone (which is normallyintact and unfractured) covered by soft tissue (mucosal tissue). In someindividuals one or more accessory ostia may also be present. Due to theanatomical position of the maxillary ostium, gravity cannot normallydrain mucus from the sinus cavity when the subject's head is erect.Thus, ciliary transport of mucus is necessary to clear mucus from thesinus cavity. The maxillary sinus cavity is normally lined with aciliated soft tissue known as mucoperiosteum. Typically, the ciliatransport mucus in a stellate or star-like pattern that originals fromthe floor of the sinus cavity, radiates over the anterior, medial,posterior, lateral and upper walls of the sinus cavity, and converges atthe natural ostium (or ostia). The mucus then drains through the naturalostium and into the nose. Also, air normally enters the maxillary sinuscavity through the ostium. When the natural ostium becomes obstructed orstenotic, the normal drainage of mucus and aeration of the maxillarysinus cavity is impaired, and chronic sinusitis can result.

Sinus surgery is sometimes performed, in which bone and soft tissue arecut away to enlarge the natural ostium. Also, the natural ostium of amaxillary sinus may be enlarged by a technique known as BalloonSinuplasty™ (Acclarent, Inc., Menlo Park, Calif.) wherein a pre-shapedguide catheter is inserted into the nose and a balloon dilation catheteris then advanced through the guide catheter. A balloon of the ballooncatheter is positioned within the maxillary sinus ostium and inflated,thereby dilation the natural ostium. This dilation typically causesfracture or other movement of bone (i.e., intact, unfractured bone)that, together with overlying soft tissue, defines the ostium. Maxillarysinus guide catheters that are useable for guiding a balloon dilationcatheter into the maxillary ostium are available commercially asRelieva® Sinus Guide Catheters (Acclarent, Inc., Menlo Park, Calif.).Details regarding the construction and configuration of these maxillaryguide catheters and details regarding balloon dilation of the maxillarysinus ostium are found in above-incorporated United States Patents andUnited States Patent Application Publications. As described in thisexample, these maxillary sinus guide catheters may also be used to guideplacement of a spacer device 11 of the present invention through amaxillary sinus ostium.

In this embodiment of the present invention, a maxillary sinus guidesuch as the type commercially available and described above is advancedinto the middle meatus MM and positioned within or in alignment with themaxillary sinus ostium. Optionally, a balloon dilation catheter (e.g.,Relieva Solo Prom™ Sinus Balloon Catheter, Acclarent, Inc., Menlo Park,Calif.) may be advanced through the maxillary sinus guide, positionedwithin the ostium, used to dilate the ostium, and then removed, leavingthe maxillary sinus guide in place. Alternatively, in some cases,surgery may have been performed to surgically enlarge the maxillaryostium prior to placement of the maxillary sinus guide catheter.

The spacer device 11, with the stylet shaft 44 inserted therein, isadvanced through the maxillary sinus guide catheter so the reservoir 14and retention members 18 enter the maxillary sinus MS. As the retentionmembers 18 emerge out of the guide catheter they will spring outwardlyto their deployed positions. When so deployed, the retention members 18will span a width that is greater than the diameter of the natural orenlarged maxillary ostium, thereby deterring slippage of the spacerdevice 11 out of the maxillary sinus MS. Thereafter, the stylet shaft 44is retracted and the stylet 40 is removed. A syringe or other infusiondevice is then attached to the Luer connector of the spacer device 11and is used to infuse a desired substance into the reservoir 14, therebycausing the reservoir to expand, as seen in FIG. 6. In some cases, abiologically inert fluid (e.g., saline solution) may be used. In othercases, a fluid containing an active substance as described above may beinfused so that the active substance will subsequently exit thereservoir 14 into the maxillary sinus MS over a desired time period.

After the desired substance has been loaded into the reservoir 14, theproximal shaft portion 12 a of the spacer device 11 is cut away orotherwise detached from the distal shaft portion 12 b. Optionally, theremaining distal shaft portion 12 b may be affixed to an adjacentanatomical structure within the nose to further secure the positioningof the implant. In the non-limiting example shown in FIG. 6, this isaccomplished by suturing the suture loop 20 to the intranasal septum S.

The implanted portion of the device 12 may remain in place for a desiredtime period and then may be removed. As explained above, in applicationswhere the reservoir 14 is loaded with a steroid and/or antimicrobialagent for treatment of chronic maxillary sinusitis, it will typically bedesirable for the implanted portion of the device 12 to remain in placewith the active substance(s) passing out of the reservoir forapproximately 14-28 days. In some subjects, the implanted portion of thedevice 12 may be allowed to remain in place to perform a spacer function(e.g., maintaining patency of the opening 70) even after any activesubstance has passed out of and been depleted from the reservoir 14.

Example 3 Placement of Spacer Through Opening in Canine or Buccal Fossa

Techniques have been well established for creating openings (e.g.,puncture tracts) between the oral cavity and the maxillary sinus.Typically, such techniques involve the creation of an opening throughthe canine or buccal fossa and into the maxillary sinus cavity. In theexample shown in FIG. 7, an opening is made through the canine fossa CFabove the teeth T and the spacer device 11 with the stylet shaft 44inserted therein is advanced through that opening such that thereservoir 14 and retention members 18 enter the sinus cavity. This maybe facilitated by insertion of a tubular guide, such as a straight rigidtube, into the canine fossa opening and then advancing the spacer device11/stylet shaft 44 through that tubular guide. As the retention members18 emerge out of the lumen of the guide 60 they will spring outwardly totheir deployed positions. When so deployed, the retention members 18will span a width that is greater than the diameter of the canine fossaopening, thereby deterring slippage of the spacer device 11 out of themaxillary sinus MS. Thereafter, the stylet shaft 44 is retracted and thestylet 40 is removed.

A syringe or other infusion device is then attached to the Luerconnector of the spacer device 11 and is used to infuse a desiredsubstance into the reservoir 14, thereby causing the reservoir toexpand. In some cases, a biologically inert fluid (e.g., salinesolution) may be used. In other cases, a fluid containing an activesubstance may be infused so that the active substance will subsequentlypass out of the reservoir 14 into the maxillary sinus MS over a desiredtime period. For example, if used to deliver Triamcinolone AcetonideInjectable Suspension, USP (Kenalog®-40, Bristol-Myers Squibb,Somerville, N.J.), the reservoir 14 may have an overall length of about16 mm and a working length (i.e., the length of the cylindrical sidewall 14 c) of about 13 mm and may be expandable to a fully expandeddiameter of 3.0 to 3.5 mm. Approximately 768 laser cut openings 31 maybe formed in the side wall of the reservoir 14 with the diameter of eachsuch opening 31 being 40 microns. This particular reservoir design, whenloaded with 0.31 to 0.35 ml of the 40 mg/ml Triamcinolone Acetonideinjectable suspension, will deliver a dose of approximately 100 μgTriamcinolone Acetonide per day for a period of 28 days into themaxillary sinus MS.

As seen in FIG. 7, after the desired substance has been loaded into thereservoir, the proximal shaft portion 12 a is cut away or otherwisedetached from the distal shaft portion 12 b. Optionally, the remainingdistal shaft portion 12 b may be affixed to an adjacent anatomicalstructure within the oral cavity to further secure the positioning ofthe implant. In the non-limiting example shown in FIG. 7, this isaccomplished by suturing the suture loop 20 to the buccal mucosa abovethe teeth T.

The implanted portion of the device 12 may remain in place for a desiredtime period and then may be removed. For example, in applications wherethe reservoir 14 is loaded with a steroid and/or antimicrobial agent fortreatment of chronic maxillary sinusitis, it will typically be desirablefor the implanted portion of the device 12 to remain in place with theactive substance(s) exiting the reservoir for approximately 14-28 days.In some subjects, the implanted portion of the device 12 may be allowedto remain in place to perform a spacer function (e.g., maintainingpatency of the opening 70) even after any active substance has passedout of and been depleted from the reservoir 14.

The term “substance,” as used herein, is to be broadly construed toinclude any feasible drugs, prodrugs, proteins, gene therapypreparations, cells, diagnostic agents, contrast or imaging agents,biologicals, etc. Such substances may be in bound or free form, liquidor solid, colloid or other suspension, solution or may be in the form ofa gas or other fluid or non-fluid. For example, in some applicationswhere it is desired to treat or prevent a microbial infection, thesubstance delivered may comprise a pharmaceutically acceptable salt ordosage form of an antimicrobial agent (e.g., antibiotic, antiviral,antiparasitic, antifungal, etc.), a corticosteroid or otheranti-inflammatory (e.g., an NSAID), a decongestant (e.g.,vasoconstrictor), a mucus thinning agent (e.g., an expectorant ormucolytic), an agent that prevents of modifies an allergic response(e.g., an antihistamine, cytokine inhibitor, leucotriene inhibitor, IgEinhibitor, immunomodulator), an anesthetic agent with or without avasoconstriction agents (e.g. Xylocalne with or without Epinephrine), ananalgesic agent, an allergen or another substance that causes secretionof mucus by tissues, hemostatic agents to stop bleeding,anti-proliferative agents, cytotoxic agents e.g. alcohol, biologicalagents such as protein molecules, stem cells, genes or gene therapypreparations, viral vectors carrying proteins or nucleic acids such asDNA or mRNA coding for important therapeutic functions or substances,cauterizing agents e.g. silver nitrate, etc.

Some non-limiting examples of antimicrobial agents that may be used inthis invention include acyclovir, amantadine, rimantadine, oseltamivir,zanamivir, aminoglycosides (e.g., amikacin, gentamicin and tobramycin),amoxicillin, amoxicillin/clavulanate, amphotericin B, ampicillin,ampicillin/sulbactam, atovaquone, azithromycin, cefazolin, cefepime,cefotaxime, cefotetan, cefpodoxime, ceftazidime, ceftizoxime,ceftriaxone, cefuroxime, cefuroxime axetil, cephalexin, chloramphenicol,clotrimazole, ciprofloxacin, clarithromycin, clindamycin, dapsone,dicloxacillin, doxycycline, erythromycin, fluconazole, foscarnet,ganciclovir, atifloxacin, imipenem/cilastatin, isoniazid, itraconazole,ketoconazole, metronidazole, nafcillin, nafcillin, nystatin, penicillinsincluding penicillin G, pentamidine, piperacillin/tazobactam, rifampin,quinupristin-dalfopristin, ticarcillin/clavulanate,trimethoprim/sulfamethoxazole, valacyclovir, vancomycin, mafenide,silver sulfadiazine, mupirocin, nystatin, triamcinolone/nystatin,clotrimazole/betamethasone, clotrimazole, ketoconazole, butoconazole,miconazole, tioconazole, detergent-like chemicals that disrupt ordisable microbes (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride,menfegol, and N-docasanol); chemicals that block microbial attachment totarget cells and/or inhibits entry of infectious pathogens (e.g.,sulphated and sulponated polymers such as PC-515 (carrageenan),Pro-2000, and Dextrin 2 Sulphate); antiretroviral agents (e.g., PMPAgel) that prevent retroviruses from replicating in the cells;genetically engineered or naturally occurring antibodies that combatpathogens such as anti-viral antibodies genetically engineered fromplants known as “plantibodies;” agents which change the condition of thetissue to make it hostile to the pathogen (such as substances whichalter mucosal pH (e.g., Buffer Gel and Acidform); non-pathogenic or“friendly” microbes that cause the production of hydrogen peroxide orother substances that kill or inhibit the growth of pathogenic microbes(e.g., lactobacillus); antimicrobial proteins or peptides such as thosedescribed in U.S. Pat. No. 6,716,813 (Lin et al.) which is expresslyincorporated herein by reference or antimicrobial metals (e.g.,colloidal silver).

Additionally or alternatively, in some applications where it is desiredto treat or prevent inflammation the substances delivered in thisinvention may include various steroids or other anti-inflammatory agents(e.g., nonsteroidal anti-inflammatory agents or NSAIDs), analgesicagents or antipyretic agents. For example, corticosteroids that havepreviously administered by intranasal administration may be used, suchas beclomethasone (Vancenase® or Beconase®), flunisolide (Nasalide®),fluticasone proprionate (Flonase®), triamcinolone acetonide (Nasacort®),budesonide (Rhinocort Aqua®), loterednol etabonate (Locort) andmometasone (Nasonex®). Other salt forms of the aforementionedcorticosteroids may also be used. Also, other non-limiting examples ofsteroids that may be useable in the present invention include but arenot limited to aclometasone, desonide, hydrocortisone, betamethasone,clocortolone, desoximetasone, fluocinolone, flurandrenolide, mometasone,prednicarbate; amcinonide, desoximetasone, diflorasone, fluocinolone,fluocinonide, halcinonide, clobetasol, augmented betamethasone,diflorasone, halobetasol, prednisone, dexamethasone andmethylprednisolone. Other anti-inflammatory, analgesic or antipyreticagents that may be used include the nonselective COX inhibitors (e.g.,salicylic acid derivatives, aspirin, sodium salicylate, cholinemagnesium trisalicylate, salsalate, diflunisal, sulfasalazine andolsalazine; para-aminophenol derivatives such as acetaminophen; indoleand indene acetic acids such as indomethacin and sulindac; heteroarylacetic acids such as tolmetin, dicofenac and ketorolac; arylpropionicacids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofenand oxaprozin; anthranilic acids (fenamates) such as mefenamic acid andmeloxicam; enolic acids such as the oxicams (piroxicam, meloxicam) andalkanones such as nabumetone) and Selective COX-2 Inhibitors (e.g.,diaryl-substituted furanones such as rofecoxib; diaryl-substitutedpyrazoles such as celecoxib; indole acetic acids such as etodolac andsulfonanilides such as nimesulide).

Additionally or alternatively, in some applications, such as those whereit is desired to treat or prevent an allergic or immune response and/orcellular proliferation, the substances delivered in this invention mayinclude a) various cytokine inhibitors such as humanized anti-cytokineantibodies, anti-cytokine receptor antibodies, recombinant (new cellresulting from genetic recombination) antagonists, or soluble receptors;b) various leucotriene modifiers such as zafirlukast, montelukast andzileuton; c) immunoglobulin E (IgE) inhibitors such as Omalizumab (ananti-IgE monoclonal antibody formerly called rhu Mab-E25) and secretoryleukocyte protease inhibitor).

Additionally or alternatively, in some applications, such as those whereit is desired to shrink mucosal tissue, cause decongestion or effecthemostasis, the substances delivered in this invention may includevarious vasoconstrictors for decongestant and or hemostatic purposesincluding but not limited to pseudoephedrine, xylometazoline,oxymetazoline, phenylephrine, epinephrine, etc.

Additionally or alternatively, in some applications, such as those whereit is desired to facilitate the flow of mucus, the substances deliveredin this invention may include various mucolytics or other agents thatmodify the viscosity or consistency of mucus or mucoid secretions,including but not limited to acetylcysteine (Mucomyst™, Mucosil™) andguaifenesin.

Additionally or alternatively, in some applications such as those whereit is desired to prevent or deter histamine release, the substancesdelivered in this invention may include various mast cell stabilizers ordrugs which prevent the release of histamine such as cromolyn (e.g.,Nasal Chrom®) and nedocromil.

Additionally or alternatively, in some applications such as those whereit is desired to prevent or inhibit the effect of histamine, thesubstances delivered in this invention may include variousantihistamines such as azelastine (e.g., Astylin®), diphenhydramine,loratidine, etc.

Additionally or alternatively, in some embodiments such as those whereit is desired to dissolve, degrade, cut, break or remodel bone orcartilage, the substances delivered in this invention may includesubstances that weaken or modify bone and/or cartilage to facilitateother procedures of this invention wherein bone or cartilage isremodeled, reshaped, broken or removed. One example of such an agentwould be a calcium chelator such as EDTA that could be injected ordelivered in a substance delivery implant next to a region of bone thatis to be remodeled or modified. Another example would be a preparationconsisting of or containing bone degrading cells such as osteoclasts.Other examples would include various enzymes of material that may softenor break down components of bone or cartilage such as collagenase (CGN),trypsin, trypsin/EDTA, hyaluronidase, and tosyllysylchloromethane(TLCM).

Additionally or alternatively, in some applications, the substancesdelivered in this invention may include other classes of substances thatare used to treat rhinitis, nasal polyps, nasal inflammation, and otherdisorders of the ear, nose and throat including but not limited toanti-cholinergic agents that tend to dry up nasal secretions such asipratropium (Atrovent Nasal®), as well as other agents not listed here.

Additionally or alternatively, in some applications such as those whereit is desired to draw fluid from polyps or edematous tissue, thesubstances delivered in this invention may include locally or topicallyacting diuretics such as furosemide and/or hyperosmolar agents such assodium chloride gel or other salt preparations that draw water fromtissue or substances that directly or indirectly change the osmolarcontent of the mucus to cause more water to exit the tissue to shrinkthe polyps directly at their site.

Additionally or alternatively, in some applications such as thosewherein it is desired to treat a tumor or cancerous lesion, thesubstances delivered in this invention may include antitumor agents(e.g., cancer chemotherapeutic agents, biological response modifiers,vascularization inhibitors, hormone receptor blockers, cryotherapeuticagents or other agents that destroy or inhibit neoplasia ortumorigenesis) such as; alkylating agents or other agents which directlykill cancer cells by attacking their DNA (e.g., cyclophosphamide,isophosphamide), nitrosoureas or other agents which kill cancer cells byinhibiting changes necessary for cellular DNA repair (e.g., carmustine(BCNU) and lomustine (CCNU)), antimetabolites and other agents thatblock cancer cell growth by interfering with certain cell functions,usually DNA synthesis (e.g., 6 mercaptopurine and 5-fluorouracil (5FU),antitumor antibiotics and other compounds that act by binding orintercalating DNA and preventing RNA synthesis (e.g., doxorubicin,daunorubicin, epirubicin, idarubicin, mitomycin-C and bleomycin) plant(vinca) alkaloids and other antitumor agents derived from plants (e.g.,vincristine and vinblastine), steroid hormones, hormone inhibitors,hormone receptor antagonists and other agents which affect the growth ofhormone-responsive cancers (e.g., tamoxifen, herceptin, aromataseingibitors such as aminoglutethamide and formestane, trriazoleinhibitors such as letrozole and anastrazole, steroidal inhibitors suchas exemestane), anti-angiogenic proteins, small molecules, genetherapies and/or other agents that inhibit angiogenesis orvascularization of tumors (e.g., meth-1, meth-2, thalidomide),bevacizumab (Avastin), squalamine, endostatin, angiostatin, Angiozyme,AE-941 (Neovastat), CC-5013 (Revimid), medi-522 (Vitaxin),2-methoxyestradiol (2ME2, Panzem), carboxyamidotriazole (CAI),combretastatin A4 prodrug (CA4P), SU6668, SU11248, BMS-275291, COL-3,EMD 121974, IMC-1C11, IM862, TNP-470, celecoxib (Celebrex), rofecoxib(Vioxx), interferon alpha, interleukin-12 (IL-12) or any of thecompounds identified in Science Vol. 289, Pages 1197-1201 (Aug. 17,2000) which is expressly incorporated herein by reference, biologicalresponse modifiers (e.g., interferon, bacillus calmette-guerin (BCG),monoclonal antibodies, interluken 2, granulocyte colony stimulatingfactor (GCSF), etc.), PGDF receptor antagonists, herceptin,asparaginase, busulphan, carboplatin, cisplatin, carmustine,cchlorambucil, cytarabine, dacarbazine, etoposide, flucarbazine,fluorouracil, gemcitabine, hydroxyurea, ifosphamide, irinotecan,lomustine, melphalan, mercaptopurine, methotrexate, thioguanine,thiotepa, tomudex, topotecan, treosulfan, vinblastine, vincristine,mitoazitrone, oxaliplatin, procarbazine, streptocin, taxol, taxotere,analogs/congeners and derivatives of such compounds as well as otherantitumor agents not listed here.

Additionally or alternatively, in some applications such as those whereit is desired to grow new cells or to modify existing cells, thesubstances delivered in this invention may include cells (mucosal cells,fibroblasts, stem cells or genetically engineered cells) as well asgenes and gene delivery vehicles like plasmids, adenoviral vectors ornaked DNA, mRNA, etc. injected with genes that code foranti-inflammatory substances, etc., and, as mentioned above, osteoclaststhat modify or soften bone when so desired.

The devices and methods disclosed herein may be used to delivercombinations of two or more substances. In one particular embodiment,the devices and methods disclosed herein may be used to deliver acombination of an anti-inflammatory agent (e.g. a steroid or an NSAID)and a mucolytic agent.

The devices and methods disclosed herein may be used to deliver gels orviscous liquids comprising one or more substances. Such gels or viscousliquids may coat and adhere to a mucous membrane and thus providesustained delivery of one or more substances to the mucous membrane. Inone embodiment, a plasticized hydrocarbon gel comprising gelatin, pectinand sodium carboxymethylcellulose and a suitable substance may bedelivered to a mucous membrane such as the mucous membrane of aparanasal sinus. Such gels can be used for sustained delivery of thesuitable substance to the mucous membrane.

The reservoir 14 of the devices described herein may optionally comprisemultiple compartments such that each compartment stores a particularsubstance formulation. The multiple compartments prevent mixing ofmultiple substance formulations before substance formulations aredelivered to the anatomy.

One or more of the substance reservoirs comprising holes or pores may befilled with a suitable substance at a sufficiently high pressure tocause a portion of the substance to squirt out of the holes or pores.This process may be used to deliver an initial bolus of the substance tothe surrounding anatomy.

One or more of the substance reservoirs disclosed herein may be filledwith a suitable substance after the substance reservoir is introduced inan anatomical region. Alternatively, one or more of the substancereservoirs disclosed herein may be filled with a suitable substancebefore the substance reservoir is introduced in an anatomical region.Alternatively, one or more of the substance reservoirs disclosed hereinmay be pre-filled with a solid, lyophilized or concentrated substance.The solid, lyophilized or concentrated substance is converted to anactive form by introducing a solvent into the substance reservoir. Thismay be done just before or after the substance reservoir is introducedin an anatomical region. Alternatively, one or more of the substancereservoirs disclosed herein may be pre-filled with an inactive form of asubstance. The inactive form of the substance is converted to an activeform by introducing an activating agent into the substance reservoir.This may be done just before or after the substance reservoir isintroduced in an anatomical region.

As described above, the implantable portion of a substance deliveringspacer device 11 may include a through lumen that may function as a ventand/or drain when such implantable portion device is implanted in thebody.

The distal-most regions of one or more substance delivery devicesdisclosed herein may comprise an atraumatic tip. The atraumatic tip isused to prevent or reduce damage to the anatomy by the distal-mostregions of the one or more substance delivery devices.

The outer surface of one of more substance delivery devices disclosedherein may comprise a coating that reduces or eliminates the risk ofencrusting of the outer surface by a biological material. In oneembodiment, the coating comprises a material that absorbs water to forma gel. Examples of such materials include, but are not limited tohyaluronic acid, etc.

One or more of the substance delivery devices disclosed herein may berefilled after a significant volume of substance filled in a substancereservoir has been delivered. For example, in one embodiment a substancedelivery device may include a proximal refilling port, which may beaccessed using a needle and syringe. Such a port may self-seal afterrefilling via the needle. One embodiment may include a grasping member,which a physician may use to grasp the device using forceps or anotherinstrument to hold the device during refilling.

One or more of the substance delivery devices disclosed herein maycomprise one or more markers to enable a user to locate and/or navigatethe substance delivery devices through the anatomy. For example, thesubstance delivery devices may comprise visual markers to enable theuser to determine the depth of insertion of the substance deliverydevices into the anatomy. In another example, the substance deliverydevices may comprise imaging markers to enable the user to locate and/ornavigate the substance delivery devices using imaging modalities such asX-rays, MRI, etc.

Although the examples above describe Triamcinolone Acetonide injectablesuspension (Kenalog® 40, Brystol-Myers Squibb Company, Princeton, N.J.)as the therapeutic agent that is loaded into and passes out of thereservoir, various other therapeutic agents may be used in addition to,or as an alternative to, this Triamcinolone Acetonide injectablesuspension. In some cases where it is desired to use the implantedspacer device 11 to deliver a steroid, the steroid may be prepared as asolution rather than a suspension. In such cases, the steroid will bedissolved in a suitable, biologically compatible solvent. For example,Cyclodextrins have been described as suitable solvents for dissolutionof at least some steroids. Khomutov, S. M., Dovbnya, D. V. and Donova,M. V., Dissolution of a Mixture of Steroids in Cyclodextrin Solutions: aModel Description; Pharmaceutical Chemistry Journal; Vol. 35, No. 11,pp. 627-629 (November, 2001).

In some instances, the devices of the present invention may be used todeliver steroids or other substances in formulations that arecommercially available as, or otherwise suitable for, intra-nasaldelivery to the nasal mucosa as nasal drops or sprays (i.e., nasalsolutions). In at least some cases, such nasal solutions are prepared sothat they are similar to nasal secretions and, thus, do not interferewith normal ciliary action. Such nasal solutions usually are isotonicand slightly buffered to a pH of 5.5 to 6.5. In addition, antimicrobialpreservatives, similar to those used in ophthalmic preparations, andappropriate drug stabilizers, if required, may be included in theformulation. Various commercial nasal preparations are known andinclude, for example, antibiotics, steroids, antihistamines,decongestants and ipitropium bromide.

Where possible and appropriate, any of the substances delivered bydevices of the present invention may optionally be in the form ofliposomes or nanoparticles (e.g., nanocapsules). The formation and useof liposomes is generally known to those of skill in the art. Liposomesare formed from phospholipids dispersed in an aqueous medium such thatthey spontaneously form multilamellar concentric bilayer vesiclessometimes referred to as multilamellar vesicles (MLVs). MLVs aretypically from 25 nm to 4 μm in diameter. When sonicated, MLVs formsmall unilamellar vesicles (SUVs) of about 200 to 500 angstroms indiameters having cores which contain the aqueous solution. In general,when dispersed in an aqueous medium, phospholipids can form variousstructures other than liposomes, depending on the molar ratio of lipidto water. At low molar lipd to water ratios, liposomes will form. Thephysical characteristics of liposomes depend on pH, tonicity and thepresence or non-presence of divalent cations. Liposomes can interactwith cells by different mechanisms, including 1) endocytosis (e.g.,phagocytosis of the liposome by cells such as macrophages andneutrophils), adsorption to the cell surface, 2) interaction withcell-surface components, 3) fusion with the plasma cell membrane byinsertion of the lipid bilayer of the liposome into the plasma membraneor 4) transfer of liposomal lipids to cellular or subcellular membranes,or vice versa. Varying the liposome formulation can alter whichmechanism(s) by which the lyposomes will interact with cells in theparanasal sinus, nasal mucosa, etc.

A nanocapsule is any nanoparticle that consists of a shell and a space,in which desired substances may be placed. Techniques for formingnanocapsules are known in the art. Polymeric nanocapsules can be made inspecific sizes and shapes. They can be produced as monodisperseparticles which have precisely defined physical and chemical propertiesand, thus, can be tailored to facilitate release of the therapeutic ordiagnostic substance in response to particular bimolecular triggeringmechanisms, such as pH, mucus flow or other conditions present withinthe paranasal sinus or other area in the ear, nose or throat where thedevice is implanted. Nanocapsules can be used in the present inventionas “smart drugs” which have specific chemical receptors or binding sitesthat will bind to specific target cells (e.g., cancer cells associatedwith sinus or nasal tumors or cells associated with inflammatoryconditions.

It is to be appreciated that the invention has been described hereabovewith reference to certain examples or embodiments of the invention butthat various additions, deletions, alterations and modifications may bemade to those examples and embodiments without departing from theintended spirit and scope of the invention. For example, any element orattribute of one embodiment or example may be incorporated into or usedwith another embodiment or example, unless otherwise specified of unlessdoing so would render the embodiment or example unsuitable for itsintended use. Also, where the steps of a method or process have beendescribed or listed in a particular order, the order of such steps maybe changed unless otherwise specified or unless doing so would renderthe method or process unworkable for its intended purpose. Allreasonable additions, deletions, modifications and alterations are to beconsidered equivalents of the described examples and embodiments and areto be included within the scope of the following claims.

What is claimed is:
 1. A system useable for treating a disorder of amaxillary sinus, the system comprising a sinus spacer device thatcomprises: (a) an elongate shaft having a lumen, a proximal end and adistal end, (b) an expandable reservoir insertable into a paranasalsinus and attached to the distal end of the elongate shaft such that asubstance may be introduced through the lumen of the elongate shaft intothe expandable reservoir, thereby causing the reservoir to expand to asize that is greater than the size of a paranasal ostium, wherein asidewall of the reservoir comprises a plurality of openings configuredto allow a substance that has been introduced into the reservoir to exitthe reservoir into the maxillary sinus via the openings, and (c) acollapsible retention structure insertable into a paranasal sinus andbiased to expand from a collapsed orientation to an expanded orientationto thereby prevent slipping of the reservoir outwardly from a paranasalostium.
 2. A system for treating a disorder of a maxillary sinus, thesystem comprising: (a) a sinus spacer device insertable into a paranasalostium, comprising: (i) an elongate shaft having a lumen, a proximal endand a distal end, (ii) an expandable reservoir attached to the distalend of the elongate shaft such that a substance may be introducedthrough the lumen of the elongate shaft into the expandable reservoir,thereby causing the reservoir to expand to a size that is greater thanthe size of a paranasal ostium, and (iii) a collapsible retentionstructure biased to expand from a collapsed orientation to an expandedorientation to thereby prevent slipping of the reservoir outwardly froma paranasal ostium, wherein the collapsible retention structurecomprises a proximal end and a distal end, wherein the distal end of thecollapsible retention structure is configured to deflect outwardly awayfrom the elongate shaft to thereby prevent slipping of the reservoirfrom the paranasal ostium, wherein the proximal end of the collapsibleretention structure is configured to remain in contact with the elongateshaft as the distal end of the collapsible retention structure deflectsoutwardly; and (b) a tubular delivery guide having a lumen through whichthe spacer device is insertable, wherein the tubular delivery guide isconfigured to constrain the collapsible retention structure in thecollapsed orientation as the sinus spacer device is inserted into aparanasal ostium.
 3. A system for treating a disorder of a maxillarysinus, the system comprising: (a) a sinus spacer device, comprising: (i)an elongate shaft having a lumen, a proximal end and a distal end,wherein the elongate shaft comprises a valve member, (ii) an expandablereservoir attached to the distal end of the elongate shaft such that asubstance may be introduced through the lumen of the elongate shaft intothe expandable reservoir, thereby causing the reservoir to expand to asize that is greater than the size of a paranasal ostium, wherein theexpandable reservoir is positioned about the elongate shaft such thatthe valve member of the elongate shaft is disposed within the expandablereservoir, wherein the valve member is configured to regulate the flowof the substance into the expandable reservoir, and (iii) a collapsibleretention structure insertable into a paranasal sinus between theexpandable reservoir and a paranasal ostium, wherein the collapsibleretention structure is biased to expand from a collapsed orientation toan expanded orientation to thereby prevent slipping of the reservoiroutwardly from a paranasal ostium; and (b) an elongate shaft having alumen through which the spacer device is insertable.